Reduced Expression Of Myc Increases Longevity And Enhances Healthspan Pdf

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Address correspondence to Haim Y. E-mail: Haim. Cohen biu.

Reducing Myc gene increases lifespan of mice by 15% on average

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells.

However, the role of this region in normal development has not been addressed. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture.

These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy. Our cells each contain close to 20, genes, which provide the instructions needed to build our bodies and keep us alive.

At any one time in the life of the cell, only some of these genes are active. The activity of each gene is constantly regulated to allow the cell to respond to changes in its environment.

Enhancers are sections of DNA, outside of the genes, that act as molecular switches controlling the activity of genes. A gene can have many such enhancers; each enhancer is linked to a particular set of signals and having multiple enhancers allows the same gene to be activated by different signals in different tissues in the body.

Changes to enhancers can have serious consequences. By altering the activity of genes, an enhancer can have widespread effects on the health and behavior of a cell, including transforming it from healthy to cancerous.

The small differences in enhancers also make some people more susceptible to cancers than others. If we can identify enhancers whose activity is commonly altered in cancers, it could be possible to target them through treatment.

Yet, it is not clear whether targeting enhancers in this way could be effectively used to treat cancer without damaging healthy cells. Now, Dave, Sur et al. The region has multiple enhancers for a cancer-linked gene called MYC and is implicated in many cancer-associated deaths every year.

This particular enhancer region is found in both humans and mice, which share many genes in common. Using genetic engineering, Dave, Sur et al.

The experiment showed that mice without the enhancer region were completely healthy. Also, when tested for cancer development, these mice were much less susceptible to several major types of cancer. This investigation reveals that it may be possible to create drugs to shut down or inhibit certain enhancers to prevent or treat cancer without damaging healthy cells. However, this is currently just one example in mice under laboratory conditions. Further research is needed to determine if a similar approach can be developed to treat patients in the clinic.

Deregulated expression of the MYC oncogene is associated with many cancer types Reviewed in Albihn et al. MYC acts primarily as a transcriptional activator that increases expression of many genes required for RNA and protein synthesis above the level that is required in resting cells.

In cancer cells, aberrantly elevated levels of MYC drive global amplification of transcription rates, providing the cells with necessary resources for rapid proliferation see, for example Brown et al.

Variants in the MYC upstream region contribute to inherited susceptibility to most major forms of human cancer, and account for a very large number of cancer cases at the population level Amundadottir et al. For example, the polymorphism rs linked to colorectal Tomlinson et al. Through computational and experimental analyses, we and others have shown that the risk allele G of rs creates a strong binding site for the colorectal-cancer associated transcription factor Tcf7l2 Pomerantz et al.

This binding site is located within the Myc enhancer element that is dispensable for mouse viability, but required for efficient Tcf7l2-driven intestinal tumorigenesis Sur et al. More recently, another enhancer element, located 1. However, in contrast to the Myc element, this element is also required for normal T-cell development.

Thus, the mechanism by which individual Myc enhancer elements contribute to normal development and tumorigenesis is still unclear.

Several studies have shown that the 8q24 region contains a large number of additional enhancer elements see, for example [ Hallikas et al. The MYC -associated super-enhancers are activated during the process of tumorigenesis Hnisz et al. Thus, MYC -associated super-enhancer activity is required for tumorigenesis, but the role of these elements in normal tissue morphogenesis and homeostasis has been unclear.

To address this problem, we have in this work generated multiple mouse strains deficient of regulatory elements upstream of the Myc promoter. By analysis of the mice, we found that the entire super-enhancer region conferring multi-cancer susceptibility contributes to MYC expression in vivo , yet is not required for mouse embryonic development and viability.

However, this region is required for the growth of normal cells in culture and cancer cells in vivo. As cultured cells are exposed to serum, which is a signal of tissue damage, this finding suggests that tumor cells and cells responding to damage signals share regulatory mechanisms that are dispensable for normal physiological growth control.

To dissect functional significance of the 8q24 region during normal development, we generated series of Myc alleles in mice using homologous recombination in ES cells. These include the Myc enhancer deletion allele we have described previously Sur et al. This site has previously been reported to be required for MYC expression Gombert and Krumm, , and to have insulator activity Gombert et al.

Each allele contained loxP site s in the same orientation to allow conditional knockouts of the enhancers, and to facilitate generation of large deletions and duplications by interallelic recombination Wu et al. All alleles were bred to homozygosity, and resulted in generation of viable mice. The lower panel shows the regional conservation probability predicted by PhastCons hg19 assembly, UCSC with non-overlapping sliding windows for the whole region and each enhancer locus with a size of bp and 10 bp, respectively.

See Figure 1—source data 1 for details. The gene body for Myc and Actb is shown below the respective panels. Error bars denote one standard deviation. Myc transcript levels in wild-type and mutant mice in Figure 1b-c. Given the very large regions that were deleted Figure 2b , we expected to see a strong phenotype.

The mice were born at the expected mendelian ratio, and both males and females were viable and fertile. Analysis of Myc expression, however, revealed a strong decrease in Myc expression in the colon and ileum of the mice not shown.

The deletion also removes several Tcf7l2 ChIP-seq peaks. Red arrowheads and horizontal lines mark the different enhancer positions. Each point represents individual mouse. Line represents the median. See Figure 2—source data 1 for details. Given that the entire Myc regulatory region spans more than 2 Mb of DNA and is located on both sides of the Myc coding region Rosenbloom et al. Still, the viability of the mice is striking, since the region deleted contains regions linked to risk for myeloma, chronic lymphocytic leukemia and pancreatic, thyroid, bladder, prostate, breast, and colon cancers Chung and Chanock, ; Sahasrabudhe et al.

To characterize the mice further, we analyzed histology and MYC expression in the tissues where these tumors originate from. This is expected since this region contains individual tissue specific regulatory elements. The expression of Myc was strongly decreased in colon, small intestine and prostate of these mice Figure 3a and not shown. Immunohistochemical analysis of MYC expression in intestine revealed strong decrease of nuclear staining, and loss of MYC expression from the transit amplifying cell compartment.

However, expression of MYC was still detected at the base of the crypt in the region where the intestinal stem cells are known to reside Figure 3b. These results are consistent with the role of the deleted region in tumorigenesis of colon and prostate. To analyze the effect of decreased MYC expression on the proliferation in the transit amplifying compartment, we performed immunohistochemistry IHC for the proliferation marker Ki Error bars indicate one standard deviation.

See Figure 3—source data 1 for details. In contrast to colon and prostate, Myc expression was not markedly affected in the bladder, and was elevated in the spleen Figure 3a. To analyze the cellular composition of the spleen, we performed flow cytometric analysis of markers for hematopoietic stem cells and lymphoid lineage cells.

In contrast to the decrease in B-cells, the T cell numbers were not affected by the deletion Figure 2—figure supplement 1a. This finding is consistent with the published data that regulatory elements controlling T-cell development and T-cell acute lymphoblastic leukemia are located 1. To identify regulatory elements that could explain the effect in B-cells, we performed ChIP-seq analysis of chromatin from LSK-Flt3 neg hematopoietic stem cells and mature B-cells isolated from wild-type mice.

This analysis identified two B-cell specific regulatory elements. The Myc 2— deletion results in loss of one of the elements, and moves the other element very close to the Myc TSS Figure 2—figure supplement 1b. Although the exact regulatory mechanism is not clear and requires further study, the above data is consistent with a role of the super-enhancer region in development of chronic lymphocytic leukemia, which is primarily a B-cell malignancy.

Based on presence of active histone marks, and undermethylation of focal elements, the super-enhancer region is active in fibroblasts from both humans and mice Figure 4a and Figure 4—figure supplement 1. The Myc super-enhancer region is also active in human fibroblasts see Figure 4—figure supplement 1. To understand the mechanism by which the deletion of the 8q24 super-enhancer region has a differential effect on growth during normal tissue homeostasis and growth under culture conditions, we subjected both the mouse tissues and cultured cells to RNA-seq analysis.

Analysis of mouse tissues confirmed the changes in Myc expression observed by qPCR Figure 5a and Figure 5—figure supplement 1. These results suggest that expression of canonical MYC target genes is not sensitive to decreases in MYC protein level during normal tissue homeostasis. Upstream regulator analysis performed using Ingenuity Pathway Analysis revealed that the highest-ranked potential regulator for the identified gene set was MYC Figure 5b.

The activation z-scores are to infer the activation states of predicted upstream regulators. Ingenuity pathway analysis performed on one of these is shown. Measured by FPKM values, the cultured wild-type fibroblasts had higher Myc mRNA levels than normal tissues, whereas the cultured null fibroblasts had Myc levels that were comparable to or lower than those of normal wild-type tissues.

The elevated Myc levels in cultured cells are caused by serum stimulation, as Myc mRNA levels are low in serum-starved fibroblasts and strongly induced by serum Ref. These results indicate that the 8q24 super-enhancer region is dispensable for normal tissue homeostasis under conditions where MYC activity is relatively low. However, the region is required for induction of MYC activity to levels that are high enough to drive the expression of MYC target genes above their basal levels during pathological growth.

We have shown earlier that deletion of a 1. The region is distinct from the colon cancer susceptibility locus that harbors Myc See Figure 6—source data 1 for details. Filled circles correspond to individual mice and red color denotes the median.

Bar equals 5 mm. Top panel shows the active enhancer elements in GP5d cells within this region as determined by ChIP-seq analysis of histone H3 lysine 27 acetylation H3K27ac. The sites of sgRNAs black lines and genotyping primers blue arrows used are indicated not to scale. Red arrows mark the enhancer regions used in this study.

Reducing Myc gene increases lifespan of mice by 15% on average

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Address correspondence to Haim Y. E-mail: Haim. Cohen biu.

So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone GH , IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. In addition, p70 ribosomal protein S6 kinase 1 S6K1 knockout leads to lifespan extension. S6K1 encodes an important kinase in the regulation of cell growth. S6K1 is regulated by mechanistic target of rapamycin mTOR complex 1. The v-myc myelocytomatosis viral oncogene homolog MYC -deficient mice also exhibits a longevity phenotype.

A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

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